From insulin receptor signalling to Glut 4 translocation abnormalities in obesity and insulin resistance

Insulin resistance is commonly associated with obesity in rodents. Using mi ce made obese with goldthioglucose (GTG-obese mice), we have shown that ins ulin resistance results from defects at the level of the receptor and from intracellular alterations in insulin signalling pathway, without major alte ration in the number of the Glut 4 glucose transporter. Activation of phosp hatidylinositol 3-kinase (PI 3-inase) was found to be profoundly affected i n response to insulin. This defect appears very early in the development of obesity, together with a marked decrease in IRS 1 tyrosine phosphorylation . In order to better understand the abnormalities in glucose transport in i nsulin resistance, we have studied the pathway leading from the insulin rec eptor kinase stimulation to the translocation of the Glut 4 containing vesi cles. This stimulation involves the activation of PI 3-kinase, which in tur ns activates protein kinase B. We have then focussed at the mechanism of ve sicle exocytosis, and more specifically at the role of the small GTPase Rab 4 in this process. We have shown that Rab4 participates, first in the intra cellular retention of the Glut 4 containing vesicles, second in the insulin signalling pathway leading to glucose transporter translocation.